During heavy exercise, blood lactate rises vs. resting values (Lactate Threshold, LT) and ventilation increases out of proportion to the metabolic rate (Ventilatory Threshold, VT). The two phenomena have been linked mechanistically under the umbrella term, "Anaerobic Threshold" (AT). Exercise above the AT is manifested by fatigue and dyspnea which occur with minimal effort in patients with heart and lung disease. The AT hypothesis states that the LT and VT are related to insufficient supply of oxygen to working muscle and increased ventilatory drive due to lactic acid, respectively. Recent data from this and other laboratories have suggested other explanations. The long-term goal of this project, therefore, is to better understand the biochemical and physiologic events during exercise responsible for the LT and VT in hopes of improving patients'exercise tolerance. This laboratory has recently utilized state of the art breath-by-breath gas exchange measurements and continuous 31P Magnetic Resonance Spectroscopy (MRS) in an attempt to link intracellular muscle metabolism with changes in blood lactate and ventilation during incremental exercise. Our published and pilot data suggest that the LT may be more related to increases in ammonia than to mitochondrial hypoxia (Systrom, Circ) and that the VT may correlate better with a rise in intramuscular hydrogen ion or blood ammonia than with a rise in blood lactate (Systrom, JAP). In the proposed human studies that follow, the purported role of tissue hypoxia in causing the LT will be examined by measuring intracellular pH with 31P MRS, blood lactate and ammonia during hypoxic exercise and after facilitation of lactate oxidation by dichloroacetate. To readdress the concept of a causal link between blood lactate and ventilation during exercise, both will be measured after manipulation of intramuscular pH by an hypoxic inspired fraction of oxygen, after dichloroacetate and training. Ammonia's role in the genesis of the LT and VT will be elucidated by increasing ammonia clearance via monosodium glutamate and citrulline in normals, glycogen depleted subjects and in patients with McArdle's disease and by examining the LT and VT in patients whose exercising muscle is incapable of NH3 production (myoadenylate deaminase deficiency). Preliminary work from this laboratory, if confirmed by the proposed studies, will offer alternative explanations for the "Anaerobic Threshold" and suggest new diagnostic and therapeutic modalities for cardiopulmonary patients. The Principal Investigator's interest in control of ventilation during exercise stems from earlier work in the Sponsor's laboratory which defined a role for central amino acid neurotransmitters in the regulation of resting ventilation. Over the past 3 years, he has used 31P MRS to continuously and noninvasively compare intramuscular metabolic events to changes in blood metabolites and ventilation during exercise. The Harvard Medical School environment is uniquely equipped to pursue the specific aims of this proposal. To our knowledge, no other facility has sufficient resources to simultaneously measure large muscle 31P MRS, blood chemistry, breath-by-breath ventilation and gas exchange.